5-43700172-TG-CC

Variant names:

• chr5-43700172-TG-CC
• NM_182977.3:c.2930_2931delTGinsCC
• NNT p.Leu977Pro

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS1 PP3

The NM_182977.3(NNT):​c.2930_2931delTGinsCC​(p.Leu977Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NNT NM_182977.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.67
• Publications: 0 publications found

Genes affected

NNT (HGNC:7863): (nicotinamide nucleotide transhydrogenase) This gene encodes an integral protein of the inner mitochondrial membrane. The enzyme couples hydride transfer between NAD(H) and NADP(+) to proton translocation across the inner mitochondrial membrane. Under most physiological conditions, the enzyme uses energy from the mitochondrial proton gradient to produce high concentrations of NADPH. The resulting NADPH is used for biosynthesis and in free radical detoxification. [provided by RefSeq, Sep 2016]

NNT Gene-Disease associations (from GenCC):

• glucocorticoid deficiency 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• familial glucocorticoid deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS1: Transcript NM_182977.3 (NNT) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182977.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NNT	NM_182977.3	MANE Select	c.2930_2931delTGinsCC	p.Leu977Pro	missense	N/A	NP_892022.2	Q13423
	NNT	NM_012343.4		c.2930_2931delTGinsCC	p.Leu977Pro	missense	N/A	NP_036475.3
	NNT	NM_001331026.2		c.2537_2538delTGinsCC	p.Leu846Pro	missense	N/A	NP_001317955.1	E9PCX7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NNT	ENST00000344920.9	TSL:1 MANE Select	c.2930_2931delTGinsCC	p.Leu977Pro	missense	N/A	ENSP00000343873.4	Q13423
	NNT	ENST00000264663.9	TSL:1	c.2930_2931delTGinsCC	p.Leu977Pro	missense	N/A	ENSP00000264663.5	Q13423
	NNT	ENST00000653251.1		c.2930_2931delTGinsCC	p.Leu977Pro	missense	N/A	ENSP00000499281.1	Q13423

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr5-43700274;